Epithelial ovarian cancer is the leading cause of death from gynecologic malignancy in the United States, with approximately 15,000 deaths per year. Platinum/taxane doublets have long been considered the standard treatment regimen for advanced-stage disease; however, recent studies have sought to improve on the outcome from this therapy. Intraperitoneal (IP) chemotherapy has been shown to yield superior progression-free survival (PFS) and overall survival (OS); however, logistical problems and toxicities have limited more widespread adoption. Recent studies have also suggested that a “dose-dense” schedule of paclitaxel in combination with carboplatin may result in improved outcomes, and the impact of biological therapies in the first-line setting is under active investigation. In the setting of recurrent disease, preliminary results suggest that novel doublet regimens such as carboplatin and pegylated liposomal doxorubicin may have similar activity to standard platinum/taxane doublets while carrying a reduced risk of allergic reactions. Additionally, targeted therapy remains an active area of investigation, with evidence of activity from agents such as PARP inhibitors, anti-angiogenics, and PI3 kinase inhibitors. Here, we review recent advances in our understanding of ovarian cancer and its treatment in both the newly diagnosed and recurrent settings.
In the United States, recommendations for post-treatment monitoring following completion of first-line therapy typically include physical examination and CA-125 monitoring every 2 to 4 months for the first 2 years, with increasing intervals between follow-up visits if there is no evidence of disease recurrence. However, data presented from the MRC OV05/EORTC 55955 study assessing the outcomes of early treatment at the time of biochemical recurrence versus delaying treatment until clinically indicated have suggested that early treatment does not alter overall survival. In this study, 1,442 women with ovarian cancer in complete remission following first-line platinum-based therapy were followed every 3 months by CA-125, but both patients and physicians were blinded to the results. At the time a subject's CA-125 rose to twice the upper limit of normal, she was randomized to either initiation of treatment or continued blinded monitoring until treatment was indicated by other clinical parameters. Of note, choice of treatment was not dictated by the study design and was at the physician's discretion; the availability of clinical trials was also not specified. Although it remains unclear how these results will affect clinical practice, these findings do suggest that treatment of asymptomatic rises in CA-125 in the absence of recurrent cancer either on physical exam and/or radiographic study may not be warranted, and that these patients should be either closely observed or enrolled in clinical trials, if available.
The majority of patients who have advanced-stage ovarian cancer at the time of initial diagnosis will experience recurrence despite the excellent response rate observed with first-line adjuvant chemotherapy. The choice of therapy for recurrent disease is often informed by the treatment-free interval (TFI) prior to disease recurrence, and recurrence is divided into platinum-sensitive (recurring greater than 6 months following treatment with a platinum-based regimen) or platinum-resistant (recurring within 6 months following prior platinum-based therapy). The TFI can predict response to additional therapy, and studies have demonstrated that patients with a longer platinum-free interval are more likely to respond to second-line platinum therapy. Given these findings, the NCCN recommends consideration of a combination platinum-based chemotherapy in patients who have disease relapse greater than 6 months following their last platinum-based therapy.
Combination Chemotherapies for Recurrent Disease
Development of therapeutic treatments for recurrent platinum-sensitive disease has focused on combination regimens, based upon the findings from four randomized phase III trials and one phase II trial, which demonstrated a benefit to combination platinum-based chemotherapy compared to single-agent therapy (see Table 3).[28-31] Earlier trials investigated the combination of carboplatin and paclitaxel[28,29]; more recently, Pfisterer et al. demonstrated that carboplatin and gemcitabine also had increased activity compared to carboplatin alone in this setting. The results of this trial led to the approval of the combination of carboplatin and gemcitabine for treatment of recurrent platinum-sensitive ovarian cancer in the United States.
Additional new doublets have been under exploration in platinum-sensitive disease. Preliminary results from the CALYPSO trial were presented at the American Society of Clinical Oncology (ASCO) meeting in June 2009. In this phase III study, 976 patients with recurrent platinum-sensitive disease were randomized to receive either carboplatin and pegylated liposomal doxorubicin (PLD) or carboplatin and paclitaxel. PFS was significantly prolonged in the carboplatin/PLD arm (11.3 months vs 9.4 months). Of additional interest, the carboplatin/PLD arm experienced only a 5% hypersensitivity rate, compared to 18% in the carboplatin/pacltiaxel arm. The final results for this trial are not yet available, but these preliminary findings suggest a possible role for carboplatin/PLD in the treatment of recurrent platinum-sensitive ovarian cancer.
Non-platinum therapies also remain under investigation. Data were presented from a randomized phase III trial comparing the novel alkaloid trabectedin in combination with PLD to PLD alone. A total of 672 patients were enrolled, and response rates for all patients were 28% in the combination arm compared to 19% in the PLD alone arm. There was no observed difference in overall survival; however, based upon the results of this trial, trabectedin has been approved in Europe for use in ovarian cancer, although the US FDA did not support approval of trabectedin in the United States.
Targeted biologic therapies are also a major area of interest in ovarian cancer research. Activity with the anti-angiogenic agent bevacizumab has been observed in phase II trials, with response rates of up to 16% in previously treated platinum-resistant recurrent ovarian cancer.[34,35] However, complications have also been observed with bevacizumab therapy in heavily pretreated populations, with one study reporting a gastrointestinal perforation rate of 11%. Patients at higher risk included those who had received three or more prior chemotherapy regimens (including the initial chemotherapy regimen used at diagnosis); the risks of bevacizumab should be carefully considered for these patients as well as those who have extensive bowel involvement or symptoms of a partial or full small bowel obstruction. The activity of cediranib, an oral VEGF kinase inhibitor, has also been demonstrated in phase II trials in recurrent ovarian cancer. A large randomized trial (ICON6) is investigating the utility of combining cediranib with carboplatin and paclitaxel therapy in women with platinum-sensitive relapsed ovarian cancer, and 450 patients are anticipated to be accrued to this study. Three arms are being studied in this trial: 1) standard carboplatin and paclitaxel with placebo therapy followed by maintenance placebo for 18 months, 2) carboplatin and paclitaxel with cediranib, followed by maintenance placebo for 18 months, and 3) carboplatin and paclitaxel with cediranib, followed by maintenance cediranib for 18 months.
One of the most exciting recent advances in targeted therapy in ovarian cancer has been the discovery and use of PARP-inhibitors. These agents work synergistically with the deficiencies of DNA-repair seen in cancers occurring in BRCA1- or BRCA2-carrier patients to damage DNA in tumor cells and cause tumor cell death. In a phase I trial of an oral PARP-inhibitor, olaparib, 12 of 19 patients who were BRCA carriers with ovarian, breast, or prostate cancer demonstrated evidence of clinical benefit from olaparib treatment. In a phase II trial of olaparib in BRCA-deficient advanced ovarian cancer, an overall response rate of 33% and a clinical benefit rate of 57.6% were observed at a dose of olaparib of 400 mg BID. Additional PARP-inhibitors are now under development from a number of pharmaceutical companies, and their roles as single-agent therapy and in combination with chemotherapy are being investigated in both BRCA-deficient and spontaneous ovarian cancer.
Other targeted agents in ovarian cancer are also under active investigation, including additional anti-angiogenic agents and agents targeted against pathways such as Notch. Additionally, there has been increasing interest in drugs that target the PI3-kinase (PI3K) / AKT pathway. Data from phase I clinical trials with PI3K/AKT-directed therapies presented at ASCO in 2009 suggest evidence of activity of these agents in ovarian cancer, and phase II trials are currently under development.
Significant advances in the understanding of the pathogenesis and management of both newly diagnosed and recurrent ovarian cancer have occurred over the past few years, making the possibility of better outcomes for women with advanced ovarian cancer a reality. Recent studies have raised the question of the ideal timing of cytoreductive surgery for newly diagnosed disease and demonstrated benefit with alternative weekly paclitaxel dosing, while ongoing studies continue to clarify the roles of IP chemotherapy and biological agents in this setting. In the setting of recurrence, new chemotherapy combinations are being explored, and investigation of the activity of various targeted agents, including anti-angiogenic agents, PARP-inhibitors, and PI3K/AKT pathway inhibitors, remains an area of active interest.
Financial Disclosure: Dr. Matulonis has received clinical research support from Genentech and AstraZeneca.
1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2009. CA: Cancer J Clin 59(4):225-49, 2009.
2. Ovary. In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. 5th ed., Philadelphia, PA: Lippincott-Raven Publishers; 1997. p. 201-6.
3. National Comprehensive Cancer Network: The NCCN Clinical Practice Guidelines in Oncology Ovarian Cancer (Version 2.2009). Available at: http://www.nccn.org. Accessed January 11, 2010.
4. McGuire WP, Hoskins WJ, Brady MF et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334(1):1-6, 1996.
5. Ozols RF, Bundy BN, Greer BE et al: Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 21(17):3194-200, 2003.
6. Levanon K, Crum C, Drapkin R: New insights into the pathogenesis of serous ovarian cancer and its clinical impact. J Clin Oncol 26(32):5284-93, 2008.
7. Fathalla MF: Incessant ovulation--a factor in ovarian neoplasia? Lancet 2(7716):163, 1971.
8. Lee Y, Miron A, Drapkin R et al: A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol 211(1):26-35, 2007.
9. Griffiths CT: Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. Natl Cancer Inst Monogr 42:101-4, 1975.
10. Vergote I, Tropacup CG, Amant F et al: EORTC-GCG/NCIC-CTG randomised trial comparing primary debulking surgery with neoadjuvant chemotherapy in stage IIIc-IV ovarian, fallopian tube and peritoneal cancer (OvCa). International Gynecologic Cancer Society 2008 Meeting: Abstract #2008_1767. Available at: http://www.igcs.org/Abstract/meeting_2008_1767.html. Accessed January 11, 2010.
11. Junor EJ, Hole DJ, McNulty L et al: Specialist gynaecologists and survival outcome in ovarian cancer: a Scottish national study of 1866 patients. Br J Obstet Gynaecol 106(11):1130-6, 1999.
12. Katsumata N, Yasuda M, Takahashi F et al: Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet 374(9698):1331-8, 2009.
13. Bookman MA, Brady MF, McGuire WP et al: Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a phase III trial of the Gynecologic Cancer Intergroup. J Clin Oncol 27(9):1419-25, 2009.
14. Herrstedt J, Huober J, Priou F et al: A randomized, phase III study (AGO-OVAR-9, GINECO-TCG, NSGO-OC-0102): gemcitabine-paclitaxel-carboplatin (TCG) versus paclitaxel-carboplatin (TC) as first-line treatment of ovarian cancer (OC): survival of FIGO stage I-IIA patients. J Clin Oncol 27(18s):Abstr LBA5510, 2009.
15. Pignata S, Scambia G, Savarese A et al: Carboplatin plus paclitaxel (CP) versus carboplatin plus stealth liposomal doxorubicin (CLD) in patients with advanced ovarian cancer (AOC): activity and safety results of the MITO-2 randomized multicenter trial. J Clin Oncol 27(18s):Abstr LBA5508, 2009.
16. Burger RA, Brady MF, Bookman MA et al: Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC) or fallopian tube cancer (FTC): A Gynecologic Oncology Group study. J Clin Oncol 28(18s):Abstr LBA1, 2010. Oral presentation accessed online at http://www.asco.org June 23, 2010.
17. ICON7 is a randomised (1:1 ratio), 2 arm, multi-centre, Gynecologic Cancer INterGroup (GCIG) open-label phase III trial designed to evaluate the safety and efficacy of adding bevacizumab, to standard chemotherapy (carboplatin and paclitaxel), in patients with advanced epithelial ovarian or primary peritoneal cancer. Available at: http://www.ctu.mrc.ac.uk/icon7/overview.asp. Accessed January 11, 2010.
18. BIBF 1120 or placebo in combination with paclitaxel and carboplatin in first line treatment of ovarian cancer. Available at: http://www.clinicaltrials.gov; access number NCT01015118. Accessed January 11, 2010.
19. Armstrong DK, Bundy B, Wenzel L et al: Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354(1):34-43, 2006.
20. Alberts DS, Liu PY, Hannigan EV et al: Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 26;335(26):1950-5, 1996.
21. Markman M, Bundy BN, Alberts DS et al: Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 19(4):1001-7, 2001.
22. National Cancer Institute. NCI Clinical Announcement on Intraperitoneal Therapy for Ovarian Cancer. Available at: http://www.cancer.gov/clinicaltrials/developments/IPchemo-digest. Accessed January 11, 2010.
23. Rao G, Crispens M, Rothenberg ML: Intraperitoneal chemotherapy for ovarian cancer: overview and perspective. J Clin Oncol 25(20):2867-72, 2007.
24. Fujiwara K, Nagao S, Kigawa J et al: Phase II study of intraperitoneal carboplatin with intravenous paclitaxel in patients with suboptimal residual epithelial ovarian or primary peritoneal cancer: a Sankai Gynecology Cancer Study Group Study. Int J Gynecol Cancer 19(5):834-7, 2009.
25. Krasner CN, Seiden MV, Fuller AF et al: Results of all-intraperitoneal carboplatin and paclitaxel regimen shows good tolerability and efficacy for advanced ovarian cancer. J Clin Oncol 25(18s): Abstr 5521, 2007.
26. Rustin GJ, Van der Burg MEL, MRC and EORTC Collaborators. A randomized trial in ovarian cancer (OC) of early treatment of relapse based on CA125 level alone versus delayed treatment based on conventional clinical indicators (MRC OV05/EORTC 55955 trials). J Clin Oncol 27(18s):Abstr 1, 2009.
27. Markman M, Rothman R, Hakes T et al: Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 9(3):389-93, 1991.
28. Parmar MK, Ledermann JA, Colombo N et al: Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 361(9375):2099-106, 2003.
29. Gonzalez-Martin AJ, Calvo E et al: Randomized phase II trial of carboplatin versus paclitaxel and carboplatin in platinum-sensitive recurrent advanced ovarian carcinoma: a GEICO (Grupo Espanol de Investigacion en Cancer de Ovario) study. Ann Oncol 16(5):749-55, 2005.
30. Pfisterer J, Plante M, Vergote I et al: Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol 24(29):4699-707, 2006.
31. Alberts DS, Liu PY, Wilczynski SP et al: Randomized trial of pegylated liposomal doxorubicin (PLD) plus carboplatin versus carboplatin in platinum-sensitive (PS) patients with recurrent epithelial ovarian or peritoneal carcinoma after failure of initial platinum-based chemotherapy (Southwest Oncology Group Protocol S0200). Gynecol Oncol 108(1):90-4, 2008.
32. Pujade-Lauraine E, Mahner S, Kaem J et al: A randomized, phase III study of carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in relapsed platinum-sensitive ovarian cancer (OC): CALYPSO study of the Gynecologic Cancer Intergroup (GCIG). J Clin Oncol 27(18s): Abstr LBA5509, 2009.
33. Monk BJ, Herzog T, Kaye S et al: A randomized phase III study of trabectedin with pegylated lioposomal doxorubicin (PLD) versus PLD in relapsed, recurrent ovarian cancer (OC). Ann Oncol 19(8suppl):viii2, LBA4, 2008.
34. Monk BJ, Han E, Josephs-Cowan CA et al: Salvage bevacizumab (rhuMAB VEGF)-based therapy after multiple prior cytotoxic regimens in advanced refractory epithelial ovarian cancer. Gynecol Oncol 102(2):140-4, 2006.
35. Cannistra SA, Matulonis UA, Penson RT et al: Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 25(33):5180-6, 2007.
36. Matulonis UA, Berlin S, Ivy P et al: Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol 27(33):5601-6, 2009.
37. Iglehart JD, Silver DP. Synthetic lethality--a new direction in cancer-drug development. N Engl J Med 361(2):189-91, 2009.
38. Fong PC, Boss DS, Yap TA et al: Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361(2):123-34, 2009.
39. Audeh MW, Penson RT, Friedlander M et al: Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer. J Clin Oncol 27(15s): Abstr 5500, 2009.
40. Wagner AJ, Von Hoff DH, LoRusso PM et al: A first-in-human phase I study to evaluate the pan-PI3K inhibitor GDC-0941 administered QD or BID in patients with advanced solid tumors. J Clin Oncol 27(15s): Abstr 3501, 2009.